RU2128507C1 - Solution for intravascular administration, method of viral and infectious sicknesses control, method of aids control, method of tuberculosis control - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: invention proposes a solution that ensures to treat patients with severe forms of sicknesses without danger of hemolysis at definite range of its concentrations. Solution has 0.005-0.23 wt.-% of at least one benzalconium fluoride of the formula:

where R - alkyl radical C₈H₁₇-C₁₈H₃₇ in vehicle that is suitable for intravascular administration. The methods of control of infectious sicknesses, AIDS and tuberculosis are carried out by an intravascular injection of proposed solution. Also, invention can be used for control of against viruses and retroviruses, especially herpes or LVA, that are responsible for AIDS. EFFECT: enhanced effectiveness of method. 19 cl, 4 dwg, 9 tbl, 9 ex

Description

 The invention relates to an intravascularly administered solution containing at least one benzalkonium fluoride.

 European patent application EP-A-0308564 already indicates the use of benzalkonium fluoride for the preparation of a general or parenteral route containing a composition containing 0.05-7%, especially of the order of 1 wt. 5%, benzalkonium fluoride intended for the control of viruses or retroviruses, especially herpes or the LVA responsible for AIDS (Acquired Immune Deficiency Syndrome).

 However, it is assumed that benzalkonium fluoride, like all benzolconium salts, which are surface-active, has a strong hemolytic ability, which prohibits its administration intravascularly. Thus, although the European patent application A-308564 refers to the general or parenteral administration of benzalkonium fluoride, in practice its use encounters this difficulty, which is considered up to now as insurmountable for two reasons: the achieved concentration in the blood to ensure activity already suggests the occurrence of hemolysis of blood; injection, even carried out very gradually, involves the creation of a locally increased structure, therefore, a hemolytic concentration, benzalkonium fluoride. In particular, the injection of this salt in concentrations of the order of 1 wt. % is impossible. However, this concentration is considered necessary to achieve sufficient activity. Consequently, they refuse the use of benzalkonium salts and, more specifically, benzalkonium fluoride, intravascularly (intravascularly), taking into account the fact that a decrease in the concentration of injection solutions will destroy any antiviral or bactericidal activity, taking into account measurable in vitro minimal inhibitory concentrations (MICs), and that even with these minor concentrations, there remains a very high risk of hemolysis, and, consequently, immediate death. Since then, the intravascular administration of benzalkonium salts, and especially benzalkonium fluoride, to a person or animal is simply ruled out.

 However, there is a continuing need to have shock therapy for viral or infectious diseases, especially those related to immune deficiency of origin, and, more specifically, for the treatment of AIDS patients in the apparent or evolving phase, who have severe “opportunistic” infections that quickly lead to dehydration and of death.

However, such shock therapy poses a number of apparently contradictory problems:
- it must act not only against pathogenic microorganisms responsible for the worsened clinical condition of the patient, but also against viruses responsible for immune deficiency (AIDS case);
- it should have a very wide spectrum of action, given the wide variety of diseases that can be the cause (death) in case of immunodeficiency;
- it, however, should be free from secondary effects, and in particular should not irritate or act on healthy organs or cells of the body, already noticeably weakened.

 Therefore, generally speaking, the aim of the invention is to find a solution to this general problem, which has not yet been solved. Therefore, the aim of the invention is to propose the treatment of patients with severe, especially multiple, viral or infectious diseases, such as diseases resulting from immunodeficiency.

 More specifically, the inventors unexpectedly found that of the quaternary ammonium compounds, benzalkonium fluoride can be effectively administered by injection intravascularly without the risk of hemolysis in a certain concentration range, in which, however, an effective effect is found.

 Therefore, it is an object of the invention to advantageously provide an injection solution for an antiviral or anti-infectious agent, such as a benzalkonium salt.

 In this regard, the invention relates to an intravascularly administered solution, characterized in that it contains about or less than 0.23 wt.% At least one benzalkonium fluoride.

где R обозначает алкильный радикал, который может изменяться от C₈H₁₇ до C₁₈H₃₇, растворенного в инъекцируемом интраваскулярно эксципиенте.

where R denotes an alkyl radical, which may vary from C ₈ H ₁₇ to C ₁₈ H ₃₇ , dissolved in an injectable intravascular excipient.

In fact, they were able to state that when the mass proportions of benzalkonium fluoride are of the order of go below 0.23%, and especially of the order of 0.20 wt. %, in general there is no danger of any hemolysis, as opposed to generally provided in the prior art. Moreover, clinical improvement can be established using concentrations above 0.05 wt. % benzalkonium fluoride. Thus, the solution according to the invention contains 0.05 - 2.3 g / l - especially of the order of 2.1 g / l - benzalkonium fluoride, preferably benzalkonium fluoride, in which R is C ₁₄ H ₂₉ .

 More specifically, the solution according to the invention contains benzalkonium fluoride in a certain concentration, so that unitary doses of the order of 0.5 to 23 mg — especially of the order of 21 mg of benzalkonium fluoride per liter of blood of the treated (treated) patient can be administered as a slow injection. So, in the case of a person with 5 liters of blood, a dose of 2.5-130 mg administered by injection is realized, especially about 105 mg, of benzalkonium fluoride.

Thus, according to the invention, two conditions must be combined so that an intravascular injection of benzalkonium fluoride can be carried out:
- the concentration of benzalkonium fluoride in the solution for injection should be below 0.23%; and
- the total amount administered by injection per liter of patient blood should remain below 23 mg.

 To determine the concentration of benzalkonium fluoride in the injection solution, blood is taken from the patient immediately before injection, this blood is subjected to hemolytic tests in vitro using solutions containing initially 0.23% benzalkonium fluoride, and the concentrations are reduced until a hemolysis-free solution is obtained.

 According to the invention, the non-hemolytic nature of the solution is controlled prior to injection by determining the hemolytic (hemolysis causing) concentration in relation to the blood of the patient.

 The solution according to the invention can be packaged in 5-15 ml ampoules - especially 10 ml - containing 0.5-23 mg - especially 21 mg per 10 ml ampoule - benzalkonium fluoride, observing a maximum value of 0.23%. And they inject 5-15 ml, especially 10 ml, of the solution per liter of patient’s blood by injection, especially 50 ml in the case of humans.

The solution according to the invention is preferably formed by benzalkonium fluoride dissolved in physiological saline. R preferably represents C ₁₂ H ₂₅ -C ₁₄ H ₂₉ . According to the invention, the solution, in addition, may include at least one metal derivative of fluorine, and, more specifically, lithium fluoride.

 The invention also relates to the use of at least one benzalkonium fluoride, the formula of which is given above, dissolved in a concentration of the order of or lower than 0.23 wt.%, In an intravascular excipient administered by injection to obtain an intravascular injectable solution intended to fight against viral or injectable, especially associated with a deficiency of immunity of origin, diseases. More specifically, the invention relates to the use of at least one such benzalkonium fluoride dissolved in a concentration of the order of or lower than 0.23 wt.%, Administered by injection of an intravascular excipient to produce an intravascular solution intended to fight AIDS in the clear or evolutionary phase. Therefore, the invention relates to a method for the treatment of viral or infectious diseases, especially those related to immunity deficiency, of diseases such as AIDS in the clear or evolutionary phase, in which case the solution according to the invention is injected intravascularly. In the method of the invention, the solution is administered by injection after determining in vivo the hemolytic ability of benzalkonium fluoride in relation to the patient’s blood, the solution administered by injection has a concentration lower than this hemolytic concentration, and by slow injection, the amount of benzalkonium fluoride is 0.5 to 23 mg per liter of blood being treated ( extractable) patient, especially and preferably 20 to 23 mg.

 Thus, when used according to the invention, 0.5 to 23 mg — especially about 21 mg — of benzalkonium fluoride dissolved in 10 ml of solution are used.

 Therefore, the invention is particularly suitable for the treatment of viral diseases that destroy immune defense, and more particularly in the form of shock therapy. According to the invention, it is also possible to effectively treat a case of Carre disease and cases of AIDS in the late phase, i.e. the development of infectious "opportunistic" diseases.

 Other characteristics and advantages of the invention follow from the examples below.

 In FIG. 1 to 4 are curves of test results for determining in vitro antiviral activity on HIV-1 virus, benzalkonium fluoride according to Example 2 below.

 Antiviral tests in vitro.

 Example 1

 The antiviral activity of tetradecyl-dimethyl-benzyl-ammonium fluoride (FBK) against vertebrate viruses is determined according to French norm AFNOR T 72 - 180, December 1989. This benzalkonium fluoride is diluted as a solution in sterile distilled water to the following concentrations: 0.02; 0.01; 0.005% (mass divided by volume).

Tests are carried out on the following strains of viruses:
picornaviridae: enterovirus polio 1, strain SABIN, cultured on a VERO cell;
- adenoviridae: type 5 adenovirus cultured on KB cell;
- herpetoviridae: herpes simplex virus type 1 (human herpes virus 1) and herpes simplex virus type 2 (human herpes virus 2), supplied by the Pasteur Institute and cultured on cell MCR-5.

Water, culture media and reagents are those recommended by the AFNOR T 72-180 standard. Virus titration is carried out by replicating (la lecture) the cytopathic experience according to the method described in AFNOR T 72-180 standard. The infection titer is calculated according to the FISHER method and VATES using the WYSHAK and DETRE tables. Results are given as the number of infectious units per ml, or plaque forming units per ml (UFP / ml)
First, the toxicity threshold (DLO) of benzalkonium fluoride is determined. Before filtration, this toxicity threshold is 0.05% (in mg per ml). After filtration, the toxicity threshold is 0.01%.

 Determine the ability of cells treated with benzalkonium fluoride to develop a viral infection and the results are presented in table 1.

The antiviral activity is then determined using the so-called "molecular sieving" method, including Sephadex LH 20 gel filtration and the use of subcytotoxic concentrations of benzalkonium fluoride. Antiviral activity is determined depending on the contact time between benzalkonium fluoride and the viral strain. Various sampling is carried out at predetermined time intervals, then they are centrifuged for 8 minutes at 1000 g, and then titrated on microplates. The control viral suspension without benzalkonium fluoride is treated in the same manner. Tables 2 to 5 show the results obtained in the form of the kinetics of inactivation of viruses depending on the time of contact with benzalkonium fluoride and on its concentration. The antiviral activity of benzalkonium fluoride (FBK) is determined by the minimum concentration and minimum time of contact with the virus, which cause a decrease in the infectious titer of viruses by a logarithmic factor of at least 4. The tests are carried out at 32 ^o C.

These experiments, therefore, confirm the antiviral activity of benzalkonium fluoride at the following concentrations (mass / volume) and contact times: 0.01% in 30 minutes against polio 1 enterovirus; 0.02% in 120 minutes with respect to type 5 adenovirus; 0.01% in 5 minutes with respect to herpes simplex virus type 1; 0.01% in 15 minutes with respect to herpes simplex virus type 2; at 32 ^o C, according to the norm AFNOR T 72 - 180.

 Example 2

 The antiviral activity of benzalkonium fluoride is tested against the HIV-1 virus (LAI strain) responsible for AIDS, supplied by the Pasteur Institute, using an infectivity test for the primary culture of activated human lymphocytes.

 The study is implemented in two stages; First, the virus is treated with a solution of benzalkonium fluoride (FBK) with a concentration of 20 μg / ml, then the residual infectivity of the treated virus is examined in a primary culture of activated human lymphocytes.

For virus treatment, the contact time, at room temperature, is 30 minutes and 60 minutes. 0.9 ml of the Virus, to which 100 μl of FBK was added, was left for 30 minutes at room temperature, then diluted in 10 ml of NTE buffer. The resulting sample is designated REV 7. A sample of REV 8 corresponds to 0.9 ml of the virus, to which 100 μl of FBK is added, left for 60 minutes at room temperature, then diluted in 10 ml of NTE buffer. After dilution in buffer, the samples are centrifuged for 35 minutes at a speed of 40,000 rpm to remove, if necessary, the product toxic for the infectivity test and concentrate the residual infectious virus. After centrifugation, the pellet was resuspended in 1 ml of culture medium, taken as an aliquot and stored at -80 ^o C.

Samples REV 1, RET 2 and REV 3. 1 are positive control samples of the experiment. REV 1 corresponds to 0.9 ml of the viral suspension, frozen at -80 ^° C. REV 2 corresponds to 0.9 ml of the viral suspension, diluted and centrifuged in the same manner as the samples REV 7 and REV 8, in order to evaluate the loss of infectivity during the centrifugation step. REV 3/1 corresponds to 0.9 ml of the virus suspension, kept at room temperature for 60 minutes (maximum duration of the study), then diluted in NTE buffer and centrifuged in the same way as the treated samples in order to evaluate the loss of infectivity due to the experimental conditions used for FBK.

 A REV 4 sample of 1 ml FBK at a concentration of 20 μg / ml, diluted in 10 ml of NTE buffer and centrifuged under the conditions described for the treated virus, is used to control possible cell toxicity due to residual infection not removed during centrifugation time of the product. This sample is therefore used as a negative control for uninfected cells of the infectivity test.

The so-called pure experiments are a search for the residual infectious ability of the samples of the treated virus against activated human PBMC lymphocytes. For this purpose, pre-stimulated lymphocytes are incubated with 1 ml of each sample of the treated virus or untreated virus, at 10 10-fold dilutions (10 ^-4 -10 ^-7 for positive control samples and 10 ^-1 -10 ^-5 for treated virus samples). The cells are centrifuged and resuspended in the amount of 10 ⁶ cells per ml in complete medium. All three or four days the cells are counted, plated again and the supernatants stored at -80 ^° C. After analyzing the results, the second experiment is carried out in an identical manner, inoculating the cells with half-diluted samples of the FBK-treated virus.

 Then measure the activity of inverse transcriptase (RT) in the supernatant of the cell culture. The supernatants stored after each stage of metamorphosis of the cells (days N 3, 7, 10, 14, 17, 21, 24 for the first experiment and days N 3, 6, 9, 13, 16 and 20 for the second experiment) also experience activity their inverse transcriptases are quantified after concentration by ultracentrifugation.

 Quantitative determinations of HIV-1 P 25 antigen are also carried out using Sandwich enzyme-linked immunosorbent assay using the same culture supernatant on days N 3, 10, 17 and 24 for the first experiment and days N 3, 9, 16 and 20 for second experiment, after cell inoculation. Use the ELAVIA Ag 1 kit sold by Diagnostic Pasteur. It is noted that control samples of REV 4 are non-toxic to the cells of the infectivity test.

 Table 6 presents the results obtained for the activity of reverse transcriptase for control samples.

From table 6 it follows that 14 days after infection, cells inoculated with dilutions below or equal to 10 ^-7 samples of REV 1 or by dilution of 10 ^-4 for samples of REV 3.1 contain (expriment viral particles in culture supernatants. In experimental conditions of infectious dilution by 100%. The titers of the control samples are respectively 10 ⁷ UI / ml for REV 1 and 10 ⁴ UI / ml for REV 2 and REV 3.1 Therefore, for the experimental control samples a decrease in the infectious titer is noted. an arithmetic factor of the order of 3 for the control sample after centrifugation and for the control sample of the virus, kept for 1 hour at room temperature and subjected to centrifugation.Fig. 1 shows that no reverse transcriptase activity was found in the supernatant of cultures inoculated with 1/10 dilution virus samples treated with FBK for 30 or 60 minutes, These results are comparable to those obtained with the control sample RFV 3.1, which has an infectious titer of 10 ⁴ UI / ml

Given these results, a second experiment is performed by inoculating PBMC using dilutions of 1/2 virus samples treated with FBK to confirm the absence of infectious viruses in the samples. Quantitative results of RT activity in culture supernatants are shown in FIG. 2. No RT activity was detected, whereas a control sample of REV 3.1 virus turned out to be positive when diluted 10 ^-5 .

In FIG. 3 presents the results of quantitative determination of antigen P 25 control samples of viruses. The amount of P 25 antigen is expressed in pg / ml and evaluated using a reference curve compiled from the standard antigen solution supplied by the manufacturer. The titers, evaluated 16 days after infection, are 10 ⁷ UI / ml for REV 1; 10 ⁵ UI / ml for REV 2 and 10 ⁴ UI / ml for KUM 3.1.

 In FIG. Figure 4 shows the quantification of P 25 antigens in supernatants of lymphocytes inoculated with diluted 1/2 solutions of virus samples treated with FBK. It is noted that samples REV 7 and REV 8 are negative for P 25 antigen. These results, therefore, confirm and refine those obtained according to viral expression by quantifying the activity of reverse transcriptase in supernatants of cultures exposed to or not treated virus.

 Thus, these experiments show that benzalkonium fluoride at a concentration of 20 μg / ml causes a loss of the infectivity of the HIV-1 virus in vitro by logarithmic factor 5 in relation to activated human lymphocytes. Thus, benzalkonium fluoride at a concentration of 20 μg / ml appears to be antiviral in vitro against the AIDS virus.

 Example 3

 Local and general tolerance to the administration of benzalkonium fluoride is intravenously tested in a dog.

 Two beagle dogs, a male and a female, with an initial weight of about 10 kg, at the age of 6 months, with good health, vaccinated and parasites removed, are placed in a vivarium. They are treated intravenously with 2 mg / kg and per day of benzalkonium fluoride diluted to a concentration of 2.10 g / l in an isotonic sterile solution of pyrogen-free sodium chloride. The solution is packaged in 10 ml ampoules, and 0.95 ml per kg and per day are injected, rotating the injections into the veins of each limb. The injection is carried out using a transcranial microperfuser mounted on a plastic syringe, and the injection is carried out intravenously slowly for about 1.5 minutes. Processing is carried out within 28 days. Urine tests are carried out before treatment, in the middle of treatment (after 14 days) and at the end of treatment.

 Similarly, blood sampling is performed from the jugular vein before treatment, 14 days later and 28 days after treatment. This blood is examined from a hematological point of view and a complete biochemical analysis is performed.

 At the end of the treatment, animals are killed and pathological and anatomical studies and weighing of the following organs are carried out: liver, kidneys, spleen, adrenal glands, testicles, ovaries, thymus, thyroid glands. Histological studies of most vital organs are also performed.

 No change in symptomatic behavior was observed during treatment. In the first two weeks, injections can be implemented without difficulty. Subsequently, edema appears.

The body weight of the animal remains stable for the duration of the experiment. The rectal temperature of the male remains stable, and the rectal temperature of the female rises by 1 ^o C during experimentation. No noticeable change in blood pressure and heart rate could be observed. Similarly, various electrocardiographic parameters remain stable throughout the duration of the experiment.

 In the case of a female, at the beginning, in the middle and at the end of the treatment, no trace of hemolysis was detected by urine tests. In the case of the presence of a large amount of blood in the urine at the beginning of treatment. The dog was placed in a diuresis cage for 48 hours. After 48 hours, a urinalysis revealed a lack of blood, traces of ketone substances, a lack of glucose and traces of proteins. Quantitative determinations of sodium and potassium underwent changes in the case of the male, but remained almost stable for the female. At the end of the treatment, no trace of blood was found in the urine taken from the male bladder at the time of autopsy.

 Of the hematological parameters, only the number of leukocytes increases after a week in the case of a female and after 4 weeks for a male. This increase corresponds to the appearance of edema on the paw.

 In the case of biochemical paramaters, an increase in the content of alkaline phosphatases and LDH can be noted. No other noticeable change was found.

 Histological examination of various organs does not show changes due to treatment, if at the same time we are not talking about local reactions at the injection sites. Thus, despite the rigor of the treatment, no noticeable toxic effect of benzalkonium fluoride administered by intravenous injection was detected.

 Example 4

 The acute toxicity of benzalkonium fluoride with a single administration of the mouse and guinea pig is determined by the method of Behrens and Karber, and the introduction is carried out intracardially, intravenously and intraperitoneally. The experimental animals are white mice and white guinea pigs, adults and young. At the administered dose, 10 animals, five females and five males are used. Benzalkonium fluoride is used in the form of a solution with a concentration of 3 g / l in a sterile isotonic solution of pyrogen-free sodium chloride. Animals are observed for 7 days after a single administration, realized with a sterile needle adapted to a 10 milliliter graduated syringe, so that each animal can be treated with a well-known dose. Animals are weighed for all days during which observation is carried out.

Determine LD ₅₀ (lethal dose 50). The results are shown in table 7.

 Thus, it is ascertained that the benzalkonium fluoride introduced intravenously, intraperitoneally or intracardially is sufficiently toxic, so that it can be administered intravascularly in doses where it is nonetheless active, namely about 20 - 23 mg per liter of blood of the patient being treated.

 Example 5

In vivo tests are performed on parvovirus-affected dogs. These dogs are treated by slow infusion of benzalkonium fluoride with C ₁₄ dissolved in a concentration of 2.1 g / l in a sterile isotonic solution of pyrogen-free sodium chloride.

 A male German shepherd weighing 20 kg at the age of eight months, affected by parvovirus (gastroenteritis with dehydration, hemorrhagic enteritis with a high content of urea) is treated with two injections with an interval of 12 hours of two ampoules. 6 days after the start of the treatment, the excellent tolerance and recovery of the dog were observed at the same time.

 A German shepherd female, aged 7 months and weighing about 10 kg, suffering from parvovirus for about 4 days (gastroenteritis with dehydration, subcomatose state, hemoconcentration, high urea, hemorrhagic salt) is treated with two injections, separated by time for 12 hours solution according to the invention. The first injection is 10 ml, and the second is 20 ml. General combined treatment is carried out within 8 days. Processing tolerance is excellent. Despite the very poor condition of the dog at the beginning of the treatment, after 20 days a complete recovery is noted.

 A male Newfoundland dog aged 6 months and weighing about 28 mg affected by parvovirus is also treated with two 10-ml time-divided injections of 10 ml by slow intravenous infusion. After the second day, blood disappears from the urine and the dogs no longer have vomiting. After the fourth day, the animal resumes eating. On the 18th day, a complete recovery was noted.

 A female Rottweiler dog aged 4 months and weighing 15 kg affected by parvovirus is also treated in the same way. After 18 days, a complete recovery is noted.

 Exactly the same treatment is carried out in the case of a female dog of the German Pointing breed at the age of 2 months, weighing about 12 kg. In the same way, recovery is noted (resumption of food intake on the 4th day and complete confirmed recovery on the 18th day).

 Three puppies (male 4 months old and weighing 12 kg; male 4 months old and weighing 7 kg; females 2 months old willow catfish 6 kg), affected by strong evolving gastroenteritis, are also treated by slow intravenous infusion of two injections with interval of 12 hours. Puppies are sick with hemorrhagic gastroenteritis. Within two days, death was ascertained.

 Thus, with the exception of three failures obtained in relation to very young and severely affected animals, dogs can be treated according to the invention for paroviruses.

 Example 6

 The invention is used to treat dogs afflicted with Carre disease. This disease, considered fatal and untreated today, is caused by an ultravirus.

 Twelve dogs are treated with one ampoule, each, with 10 ml of a solution of benzalkonium fluoride with a concentration of 2.1 g / l per 20 kg of animal weight. The injection is carried out once a day for three days. Dogs are subjected to combined treatments (vitamins, antibiotics, vaccines ...).

 The treatment turned out to be effective for seven dogs whom they were able to save and for which, after 18 days, a complete recovery was detected.

Of the seven cured dogs, five of them come from a pack in which two deaths have already been ascertained, and are very affected by the disease. They were already subjected to the first, which turned out to be ineffective, processing. Symptoms are especially suppuration from the nostrils, cough, diarrhea, purulent conjunctivitis, fever (fever) with a temperature of 40 - 40.5 ^o C on average. The processing efficiency is therefore particularly surprising.

 Five other treated dogs had all the neural-origin symptoms (general tremor) and could not be treated. Therefore, the invention allows the treatment of cases of Carre disease that are not accompanied by symptoms of a nervous origin.

 Example 7

 The in vitro hemolytic concentration of benzalkonium fluoride is determined in the case of human blood, blood of guinea pigs and rabbits, and the blood contains all components.

 This experiment is carried out using a peripheral anemia test procedure in a hospital. Use 3 dilutions of a solution of benzalkonium fluoride per liter: 300 mg / l; 150 mg / l and 75 mg / l; in a sterile isotonic solution of pyrogen-free sodium chloride. Each solution of three dilutions is mixed with an equal volume of blood of three species (human, guinea pig and rabbit). The mixture is slowly stirred for 5.5 minutes, then centrifuged for 3 minutes at a speed of 35,000 rpm. Hemolysis is expressed in a more or less intense red staining of the plasma supernatant. The real test concentrations of benzalkonium fluoride are therefore 150 ppm. (ppm), 75 ppm and 35.5 ppm Each experiment is repeated twice.

 Having not detected hemolysis at a concentration of 37.5 mg / l, new tests are carried out on six samples of human blood under the same conditions with a concentration of benzalkonium fluoride of 20 mg / l and 35 mg / l.

 Table 8 summarizes the results.

 Thus, benzalkonium fluoride at a concentration equal to or lower than 20 mg / l does not cause hemolysis of human blood, and this is with a good safety range.

 According to the invention, however, before the injection, the hemolytic concentration of benzalkonium fluoride in relation to the blood of the patient being treated can be easily checked.

 Example 8

 AIDS patients in the evolutionary or final phase are treated with a solution containing 2.1 g / l benzalkonium fluoride. Before injection, determine the hemolytic concentration of benzalkonium fluoride and make sure that it is much higher than the solution used.

A man aged 37 years weighing 70 kg has the following symptoms: asthenia, exhaustion, candidiasis of the oral cavity, fever with a temperature of 39.7 ^o C, ELISA tests ("enzyme immunosorbent assay) and Western blotting (confirmation test) positive, the number of CD ₄ (receptors on the surface of T lymphocytes, responsible for the regulation of immune plumb) is less than 200 (normal value is about 1000). The patient is treated by slow intravenous injection of 50 ml of c ₁₄ benzalkonium fluoride at a concentration of 2.1 g / l, repeated every twelve hours as TLDs treatments for three days, separated by an interval of 5 days of observation. In spite of the pain at the time of injection, appears at the end of the second course of treatment, observation of one month and seven months after treatment show good general condition of the patient, who can resume their activity. The number of CD ₄ rises to 600.

A man aged 28 years weighing 57 kg has the following symptoms: asthenia, exhaustion, vomiting, diarrhea, candidiasis of the oral cavity, fever with a temperature of 39.5 ^o C, the patient is completely recumbent, ELISA and Western blotting tests are positive, CD ₄ = 20. This patient is subjected to two courses of treatment for 3 days, as described above. On the 10th day after the start of treatment, a marked improvement in the general condition, the disappearance of fever, vomiting and diarrhea and weight recovery (59.6 kg) are noted. The patient can rise and walk.

A man aged 44 years old weighing 78 kg has the following symptoms: asthenia, anorexia, insomnia, fever with a temperature of 39.7 ^o C, ELISA and Western blotting tests are positive. the number of CD ₄ is 650. The patient is treated by slow intravenous injection of 50 ml of benzalkonium fluoride with C ₁₄ at a concentration of 2.1 g / l, repeated every eight hours for three days, with additional antibiotic treatment (based on doxycycline), two gelatin capsules with the medicine every evening.

 On the sixth day after the start of treatment (treatment), the fever (fever) disappears. Two months after the start of treatment, a gradual disappearance of asthenia is noted. In the fourth month, the patient, to whom the normal general condition has returned, restores his life activity.

A 42-year-old man weighing 52 kg has the following symptoms: asthenia, anorexia, perspiration, inguinal adenopathy, diarrhea, severe headaches, candidiasis of the oral cavity, fever with a temperature of 39 ^o C, ELISA and western blocking tests are positive, CD number ₄ = 200. The patient is treated by a course of treatment for three days with benzalkonium fluoride with C ₁₄ at a concentration of 2.1 g / l in the form of slow intravenous injections every 12 hours. Starting from the third day, a distinct decrease in heat (fever) is noted. 3.5 months after the start of treatment, the patient has a good general condition, weight 56 kg, the number of CD ₄ rises to 700 and no clinical symptoms.

 Example 9

 The activity of in vitro benzalkonium fluoride on tuberculous mycobacteria (wild strain) is determined.

This experimentation is carried out by the BOWEINSTEIN JENSEN medium surface impregnation procedure. The amount of active substance absorbed by the medium is expressed in cm ² .

The used volume of the corresponding dilution of benzalkonium fluoride is 0.25 ml per tube with medium to achieve concentrations of benzalkonium fluoride 0.1, 0.2 and 0.3% per surface in cm ² of BOWEINSTEIN JENSEN medium.

 For each test series, a control tube without benzalkonium fluoride is used.

 Three series of tests are carried out with dilutions of 0.1, 0.01 and 0.001 of the prepared stock solution of the Bacterium Tuberculosus strain with a concentration of 1 mg / ml.

 All tests are carried out twice.

After incubation for 4 weeks at 37 ^° C, the results show culture inhibition using concentrations of benzalkonium fluoride 0.1, 0.2 and 0.3% per surface in cm ² of BOWEINSTEIN JENSEN medium and this is observed for three dilutions of 0.1, 0.01 and 0.001 of Bacterium Tuberculosis uterine culture .

 Table 9 presents the results.

Claims (19)

1. A solution for intravascular administration containing 0.005 to 0.23 wt.% At least one benzalkonium fluoride of the formula

where R is an alkyl radical of C ₈ H ₁₇ - C ₁₈ H ₃₇ ,
in an excipient suitable for intravascular administration.  2. The solution according to claim 1, containing 0.2 wt.% Benzalkonium fluoride.  3. The solution according to claim 1 or 2, containing more than 0.05 wt.% Benzalkonium fluoride. 4. A solution according to any one of claims 1 to 3, containing benzalkonium fluoride, in which R is C ₁₂ H ₂₅ - C ₁₄ H ₂₉ . 5. The solution according to any one of paragraphs. 1, 3 and 4, containing 0.21 wt.% Benzalkonium fluoride, in which R is equal to C ₁₄ H ₂₉ .  6. A solution according to any one of claims 1 to 5, packaged in ampoules of 5-6 ml, preferably 10 ml, containing 0.5-23 mg, preferably 21 mg, benzalkonium fluoride.  7. The solution according to any one of claims 1 to 6, in which the excipient is physiological saline.  8. The solution according to any one of claims 1 to 7, further containing at least one metal derivative of fluorine.  9. The solution of claim 8, in which the metal derivative of fluorine is lithium fluoride.  10. A method of combating viral and infectious diseases, preferably due to immunodeficiency, characterized in that it is carried out by intravascular injection of a solution according to claims 1 to 9.  11. A method of combating AIDS, characterized in that it is carried out by intravascular injection of a solution according to claims 1 to 9.  12. A method of combating tuberculosis, characterized in that it is carried out by intravascular injection of a solution according to claims 1 to 9.  13. The control method according to any one of claims 10 to 12, characterized in that a solution containing 0.2 wt.% Benzalkonium fluoride is used.  14. The control method according to any one of claims 10 to 12, characterized in that the solution is injected slowly until a dose of 0.5–23 mg benzalkonium fluoride is reached, preferably 21 mg, per liter of blood of the patient being treated. 15. The control method according to any one of claims 10 to 12, characterized in that they use a solution containing benzalkonium fluoride having R equal to C ₁₂ H ₂₅ - C ₁₄ H ₂₉ .  16. The control method according to any one of claims 10 to 12, characterized in that they use a solution containing 0.5 to 23 mg, preferably 21 mg, of benzalkonium fluoride in a volume of 10 ml.  17. The control method according to any one of claims 10 to 12, characterized in that benzalkonium fluoride is used in physiological saline.  18. The control method according to any one of claims 10 to 12, characterized in that they use a solution of benzalkonium fluoride, optionally containing a metal derivative of fluorine.  19. The control method according to p, characterized in that the metal derivative of fluorine is lithium fluoride.

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